Structure and Absolute Configuration of the Ansamycin Antibiotic Awamycin

Abstract

The structure and absolute configuration (3) of the biologically active ansamycin antibiotic awarnycin have been determined from X-ray diffraction data recorded at 129 K. Crystals are monoclinic, space group P2′2′2′, with a 25.426(3), b 30.823(2), c 13.592(1) A, and contain two molecules of the antibiotic and eleven solvent molecules (two water and nine ethanol) in each asymmetric scattering unit. The structure was solved with SHELXS and refined by full-matrix least-squares analysis to R 0.076 ( R_w 0.090) for 7308 reflections and 1174 refined parameters. Analysis of observed and calculated Bijvoet differences with the statistic Χ² defines the absolute configuration of awamycin as 20R,21R,22R,23R,24R,25R,26R,27S,28S and the helicity as P. This is the first crystal structure analysis of an underivatized ansamycin antibiotic of the subgroup possessing an 18-membered ansa chain, and the first such analysisof an underivatized ansarnycin antibiotic in which it has been possible to assign absolute stereochemistry by the Bijvoet method. The constitution and absolute configuration of awamycin are compared with those of related ansarnycins carrying 18- and 19-membered ansa chains, and the tertiary structures of awarnycin and of several rifamycins and variants are analysed in relation to the arrangement of oxygen functions required for antibiotic activity.